Compounds and methods for inhibiting the interaction of BCL proteins with binding partners

ABSTRACT

The present invention relates to heterocyclic compounds that bind to Bcl proteins and inhibit Bcl function, compositions comprising such compounds, and methods for treating and modulating disorders associated with hyperproliferation, such as cancer.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/750,987, filed Dec. 16, 2005.

BACKGROUND OF THE INVENTION

The present invention generally relates to heterocyclic compounds usefulfor treating cancer.

Apoptosis, or programmed cell death, is important for normalembryological/anatomical development, host defense and suppression ofoncogenesis. Faulty regulation of apoptosis has been implicated incancer and in many other human diseases which result from an imbalancebetween the process of cell division and cell death. A central checkpoint of apoptosis is the regulation of cytochrome c release frommitochondria. Cytochrome c release is regulated, in part, by Bcl-2family members. The Bcl-2 family of proteins includes bothanti-apoptotic molecules, such as Bcl-2 and Bcl-XL, and pro-apoptoticmolecules, such as Bax, Bak, Bid and Bad. Bcl-2 contributes to cancercell progression by preventing normal cell turnover caused byphysiological cell-death mechanisms. Over-expression of Bcl-2 has beenobserved in 70% of breast cancer and many other forms of cancer.

Various small molecules have been shown to inhibit the function ofBcl-2. Nevertheless, the need exists for additional small organicmolecules that bind to Bcl-2 and block its anti-apoptotic function incancer and promote cell death in tumors.

SUMMARY OF THE INVENTION

One aspect of the invention relates to heterocyclic compounds andpharmaceutically acceptable salts of these compounds. In certaininstances, the heterocyclic compound comprises a nitrogen containingfive membered heterocyclic core, such as a pyrrolidine, oxazolidine,thiazolidine, imidazolidine, or pyrazolidine, and unstaturatedderivatives thereof. In other instances, the heterocyclic compoundcomprises a nitrogen containing six membered heteocyclic core, such as apiperidine, morpholine, piperazine, thiopiperazine, and unsaturatedderivatives thereof. In certain instances, the five or six memberedheterocylic ring may be susbstitued with an oxo or thioxo group (e.g.,pyrrolidone, oxazolidinone, imidazolidone, thiazolidone); a nitrogenatom of the heterocyclic ring is bonded to a substituted aralkyl group;the substituted aralkyl group is a substituted benzyl group; theheterocyclic ring is substituted with a hydroxy methyl or hydroxy ethylgroup; the heterocyclic ring is substituted with a hydroxy methyl and ahydroxy ethyl group; and/or the heterocyclic ring is substituted with anamide group.

Another aspect of the invention relates to pharmaceutical compositionscomprising one or more of the heterocyclic compounds of the invention,or salts thereof. A further aspect of the present invention relates to amethod of using the above compounds, or pharmaceutically acceptablesalts thereof, alone or in combination with other agents to treatcancer. Specifically, the invention provides a therapeutic methodcomprising treating a condition characterized by the pathologicalproliferation of mammalian cells by administering an effective amount ofa compound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The definitions of terms used herein are meant to incorporate thepresent state-of-the-art definitions recognized for each term in thechemical and pharmaceutical fields. Where appropriate, exemplificationis provided. The definitions apply to the terms as they are usedthroughout this specification, unless otherwise limited in specificinstances, either individually or as part of a larger group.

As used herein, the definition of each expression, e.g., alkyl, m, n,etc., when it occurs more than once in any structure, is intended to beindependent of its definition elsewhere in the same structure.

The term “acylamino” refers to a moiety that may be represented by thegeneral formula:

wherein R50 is as defined below, and R54 represents a hydrogen, analkyl, an alkenyl or —(CH₂)_(m)-R61, where m and R61 are as definedbelow.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond respectively.

The terms “alkoxyl” or “alkoxy” refers to an alkyl group, as definedabove, having an oxygen radical attached thereto. Representative alkoxylgroups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. In certain embodiments, a straightchain or branched chain alkyl has 30 or fewer carbon atoms in itsbackbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain),and in other embodiments 20 or fewer. Likewise, in certain embodimentscycloalkyls have from 3-10 carbon atoms in their ring structure, and inother embodiments have 5, 6 or 7 carbons in the ring structure. Incertain embodiments cycloalkyls, bicycloalkyls, and polycylcloalkyls canbe further subsittured with one or more alkyl subsituents.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. In certain embodiments, the“alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl,—S-alkynyl, and —S—(CH₂)_(m)-R61, wherein m and R61 are defined below.Representative alkylthio groups include methylthio, ethyl thio, and thelike.

The term “amido” is art recognized as an amino-substituted carbonyl andincludes a moiety that may be represented by the general formula:

wherein R50 and R51 are as defined below. Certain embodiments of theamide in the present invention will not include imides which may beunstable.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R50, R51 and R52 each independently represent a hydrogen, analkyl, an alkenyl, —(CH₂)_(m)-R61, or R50 and R51, taken together withthe N atom to which they are attached complete a heterocycle having from4 to 8 atoms in the ring structure; R61 represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zeroor an integer in the range of 1 to 8. In other embodiments, R50 and R51(and optionally R52) each independently represent a hydrogen, an alkyl,an alkenyl, or —(CH₂)_(m)-R61. Thus, the term “alkylamine” includes anamine group, as defined above, having a substituted or unsubstitutedalkyl attached thereto, i.e., at least one of R50 and R51 is an alkylgroup.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group (e.g., an aromatic or heteroaromatic group).

The term “aryl” as used herein includes 5-, 6- and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, anthracene, naphthalene, pyrene,pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole,pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.Those aryl groups having heteroatoms in the ring structure may also bereferred to as “aryl heterocycles” or “heteroaromatics.” The aromaticring may be substituted at one or more ring positions with suchsubstituents as described above, for example, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,heterocyclyl, aromatic or heteroaromatic moieties, —CF3, —CN, or thelike. The term “aryl” also includes polycyclic ring systems having twoor more cyclic rings in which two or more carbons are common to twoadjoining rings (the rings are “fused rings”) wherein at least one ofthe rings is aromatic, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The term “carboxyl” is includes such moieties as may be represented bythe general formulas:

wherein X50 is a bond or represents an oxygen or a sulfur, and each ofR55 and R56 represents independently a hydrogen, an alkyl, an alkenyl,—(CH₂)_(m)-R61or a pharmaceutically acceptable salt, where m and R61 aredefined above.

The term “diradical” or “bivalent” as used herein are usedinterechangeably and refer to any of a series of divalent groups fromalkyl, alkenyl, alkynyl, alkylamino, alkoxyl, cycloalkyl,heterocycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, andheteroaralkyl groups. For example,

is a bivalent alkyl or alkyl diradical;

is also a bivalent alkyl or alkyl diradical;

is a bivalent aryl or aryl diradical;

is a bivalent aralkyl or aralkyl diradical; and

is a bivalent (alkyl)heteroaralkyl or (alkyl)heteroaralkyl diradical.Typical examples include alkylenes of general structure (CH₂)_(X) whereX is 1-6, and corresponding alkenylene and alkynylene linkers having 2-6carbon atoms and one or more double or triple bonds; cycloalkylenegroups having 3-8 ring members; and aralkyl groups wherein one openvalence is on the aryl ring and one is on the alkyl portion such as

and its isomers.

The term “haloalkyl”, as used herein, refers to an alkyl group whereanywhere from 1 to all hydgrogens have been replaced with a halide. A“perhaloalkyl” is where all of the hydrogens have been replaced with ahalide.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Examples of heteroatoms include boron,nitrogen, oxygen, phosphorus, sulfur and selenium.

The terms “heterocyclyl” or “heterocyclic group” refer to 3- to10-membered ring structures, more preferably 3- to 7-membered rings,whose ring structures include one to four heteroatoms. Heterocycles canalso be polycycles. Heterocyclyl groups include, for example, thiophene,thianthrene, furan, pyran, isobenzofuran, chromene, xanthene,phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,indole, indazole, purine, quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,phenanthroline, phenazine, phenarsazine, phenothiazine, furazan,phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine,piperazine, morpholine, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. The heterocyclic ringmay be substituted at one or more positions with such substituents asdescribed above, as for example, halogen, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic orheteroaromatic moiety, —CF3, —CN, or the like.

As used herein, the term “nitro” means —NO2; the term “halogen”designates —F, —Cl, —Br or —I; the term “sulfhydryl” means —SH; the term“hydroxyl” means —OH; and the term “sulfonyl” means —SO2—.

The term “oxo” refers to a carbonyl oxygen (═O).

The terms “polycyclyl” or “polycyclic group” refer to two or more rings(e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings, e.g., the rings are “fused rings”. Rings that are joined throughnon-adjacent atoms are termed “bridged” rings. Each of the rings of thepolycycle may be substituted with such substituents as described above,as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromaticmoiety, —CF3, —CN, or the like.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991).

The terms “triflyl”, “tosyl”, “mesyl”, and “nonaflyl” refer totrifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, andnonafluorobutanesulfonyl groups, respectively. The terms “triflate”,“tosylate”, “mesylate”, and “nonaflate” to trifluoromethanesulfonateester, p-toluenesulfonate ester, methanesulfonate ester, andnonafluorobutanesulfonate ester functional groups and molecules thatcontain said groups, respectively.

The term “thioxo” refers to a carbonyl sulfur (═S).

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl,phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc.

Certain compounds may exist in particular geometric or stereoisomericforms. The present invention contemplates all such compounds, includingcis- and trans-isomers, R- and S-enantiomers, diastereomers,(d)-isomers, (I)-isomers, the racemic mixtures thereof, and othermixtures thereof, as falling within the scope of the invention.Additional asymmetric carbon atoms may be present in a substituent suchas an alkyl group. All such isomers, as well as mixtures thereof, areintended to be included in this invention.

The phrases “Bcl-mediated disorder” and “disorder mediated by cellsexpressing Bcl proteins” refer to pathological and disease conditions inwhich a Bcl protein plays a role. Such roles may be directly related tothe pathological condition or may be indirectly related to thecondition. The feature common to this class of conditions is that theymay be ameliorated by inhibiting the activity of, function of, orassociation with Bcl proteins.

As used herein, the terms “Bcl” and “Bcl protein” are intended toencompass one or more of the Bcl-2 subfamily of anti-apoptotic proteinsBcl-2, Bcl-w, Mcl-1, Bcl-XL, A1, Bfl1, Bcl-B, BOO/DIVA, and theirhomologues.

Synthesis of Heterocyclic Compounds

In certain instances, the heterocyclic compounds of the presentinvention are five membered heterocycles. The five membered heterocyclescan be prepared from the reaction of triphosgene, thiophosgene,thionylchloride, sulfonylchloride and the like, and 1,2 amino alcohols,1,2 amino thiols, or 1,2 diamines. In certain instances, the fivemembered heterocycles of the present invention can be prepared by thereaction of an 1,2 amino alcohol, 1,2 amino thiol, or 1,2 diamine withan aldehyde or ketone. In certain instances, the heterocycles of thepresent invention can be synthesized from cyclizations of gamma aminoacids to afford 2-pyrridones. In certain instances, the five memberedheterocycles of the present invention can be synthesized using a [3+2]cycloaddition reaction between an azaallyl anion or azomethine ylide andan alkene. The azomethine ylide substrate and alkene may containfunctional groups suitable for chemical derivatization followingsynthesis of a pyrrolidine core. In certain instances, a Lewis acid,e.g., AgOAc, is added to the reaction. In certain instances, thereaction mixture is subjected to heat. In general, the subject reactionsare carried out in a liquid reaction medium, but can be carried out on asolid support. In certain instances, the heterocycles can be synthesizedfrom the [3+2] cycloaddition of nitrones and allylic alcohols. The5-methyl alcohol on the resulting cycloadducts can then be reacted withmesyl chloride to yield a 5-methyl-mesylate-isoxazolidine. Upon exposureto SmI, the N—O bond of the isoxazolidine is reduced and the aminespontaneously cyclizes to form a pyrrolidine, as described in theexamples below (see also, U.S. Ser. No. 11/156,364, filed Jun. 17, 2005,Publication No. 20060025460, herein incorporated by reference in itsentirety). Typically, the N—O bond reduction takes place in a proticsolvent, such as methanol.

In certain embodiments, the heterocyclic compounds of the presentinvention are six membered heterocycles. These compounds can be madeusing a number of methods in the art. For example, the heterocycles canbe synthesized using annulation strategies from acyclic precursorscontaining two nucleophilic species separated by three carbons. Forexample, 1,3 diamines, 1,3 amino alcohols, 1,3 diols , 1,3 dithions, 1,3amino thiols, or 1,3 thiol alcohols can be cyclized using sulfonylchloride, phosgene, or thiophosgene to generate a 6 membered ring.Likewise, six memebered rings can be made by intermolecular orintramolecular condensation reactions, or [4+2] cycloaddition reactions.In addition, a number of six membered heterocycles are commerciallyavailable and can be modififed to yield the compounds of the presentinvention.

Following synthesis of the heterocyclic core, the heterocyclic compoundsmay be derivatized using a variety of functionalization reactions knownin the art. Representative examples include palladium coupling reactionsto alkenylhalides or aryl halides, oxidations, reductions, reactionswith nucleophiles, reactions with electrophiles, pericyclic reactions,installation of protecting groups, removal of protecting groups, and thelike.

The heterocyclic compounds of the invention bind to one or more Bclproteins and block Bcl anti-apoptotic function in cancer cells and tumortissue that express the Bcl protein. In certain embodiments, compoundsof the invention selectively inhibit the anti-apoptotic activity of onlyone member of the Bcl-2 subfamily of anti-apoptotic proteins. Theheterocyclic compounds of the invention can be used to treat a patientsuffering from a disease related to Bcl. In certain instances, theheterocyclic compounds of the invention are used to treat a patientsuffering from cancer.

Biological Activity Analysis

The following in vitro binding and cellular assays can be used todetermine the activity and specificity of compounds of the presentinvention to bind to Bcl-2 and inhibit Bcl-2 function in a cell.

Bcl-2 Binding Assay

Bcl-2 and Bcl-xL binding can be determined using a variety of knownmethods. One such assay is a sensitive and quantitative in vitro bindingassay using fluorescence polarization (FP) described by Wang, J.-L.;Zhang, Z-J.; Choksi, S.; Sjam. S.; Lu, Z.; Croce, C. M.; Alnemri, E. S.;Komgold, R.; Huang, Z. Cell permeable Bcl-2 binding peptides: a chemicalapproach to apoptosis induction in tumor cells. Cancer Res. 2000, 60,1498-1502).

Cell Based Assays

The ability of heterocyclic compounds of the present invention toinhibit cell-viability in cancer cells with Bcl-2 proteinover-expression was demonstrated. When RL-cells are exposed to theheterocyclic compounds of the present invention, the inhibitors show adose-dependent cell-killing in the Alamar blue cytoxicity assay withIC₅₀ values of from about 100 μM to about 1 μM (See Examples). WhenPanc1 cells are exposed to the heterocyclic compounds of the presentinvention in combination with camptothecin, the inhibitors show asynergistic dose-dependent cell killing in the propidium iodideexclusion cell survival assay with IC₅₀ values of from about 100 μM toabout 1 μM (See Examples).

Bcl-2 inhibitors have been shown to be active against a number of cancercell lines as single agent, including, but not limited to, breast cancer(US 2003/0119894, published PCT applications WO 02/097053 and WO02/13833; all of which are hereby incorporated by reference), lymphomas(Nature (2005) 435, 677-681), small cell lung cancer (Nature (2005) 435,677-681), head and neck cancer (published PCT application WO 02/097053;hereby incorporated by reference), and leukemias (published PCTapplication WO 02/13833; hereby incorporated by reference).

Bcl-2 inhibitors have been shown to be active against a number of cancercell lines in combination with other anticancer agents and radiation,including, but not limited to, breast cancer (With docetaxel, publishedPCT application WO 02/097053; hereby incorporated by reference),prostate cancer (With docetaxel, published PCT application WO 02/097053;hereby incorporated by reference), head and neck cancer (With docetaxel,published PCT application WO 02/097053; hereby incorporated byreference), and non small-cell lung cancer (With paclitaxel, Nature(2005) 435, 677-681). In addition to the aforementioned combinationchemotherapeutics, small molecule inhibitors of Bcl-2 proteins displaysynergy with other anticancer agents, including, but not limited toetoposide, doxorubicin, cisplatin, paclitaxel, and radiation (Nature(2005) 435, 677-681).

Methods of Therapy and Treatment

The present invention further provides methods for treating and reducingthe severity of cancer as well as other Bcl-mediated disorders orconditions.

Cancers or neoplastic diseases and related disorders that can be treatedby administration of compounds and compositions of the presentinvention, include, but are not limited to those listed below (for areview of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia): Leukemia (including acute leukemia,acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic,promyelocytic, myelomonocytic, monocytic, erythroleukemia, chronicleukemia, chronic myelocytic (granulocytic) leukemia, and chroniclymphocytic leukemia); Polycythemia vera; Lymphoma (including Hodgkin'sdisease and non-Hodgkin's disease); Multiple myeloma; Waldenstrom'smacroglobulinemia; Heavy chain disease; and Solid tumors (includingfibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterinecancer, testicular tumor, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, and retinoblastoma).

In a preferred embodiment, the compounds of the present invention areused to treat cancers including, but not limited to, lymphomas(preferably follicular lymphoma, diffuse large B-cell lymphoma, mantlecell lymphoma, or chronic lymphocytic leukemia), prostrate cancer (morepreferably hormone insensitive), breast cancer (preferably estrogenreceptor positive), neuroblastoma, colorectal, endometrial, ovarian,lung (preferably small cell), hepatocellular carcinoma, multiplemyeloma, head and neck or testicular cancer (preferably germ cell).

Treatment of Cancer in Combination with Chemotherapy or Radiotherapy

One or more compounds of the present invention can also be used to treator prevent cancer or neoplastic disease in combination with one or moreanti-cancer, chemotherapeutic agents including, but not limited to,methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea,cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin,carboplatin, mitomycin, dacarbazine, procarbizine, etoposides,prednisolone, dexamethasone, cytarbine, campathecins, bleomycin,doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin,mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine,paclitaxel, docetaxel, 5-FU, epipodophyllotoxin, camptothecin, 17-AAG,or cyclophosphamide. In a preferred embodiment, one or more compound ofthe present invention is used to treat or prevent cancer or neoplasticdisease in combination with one or more chemotherapeutic or otheranti-cancer agents including, but not limited to those shown below:

-   Radiation, e.g., γ-radiation; Nitrogen mustards (including    cyclophosphamide, Ifosfamide, trofosfamide, Chlorambucil,    Estramustine, and melphalan); Nitrosoureas (including carmustine    (BCNU) and Lomustine (CCNU)); Alkylsulphonates (including busulfan    and Treosulfan); Triazenes, such as Dacarbazine; Platinum containing    compounds (including Cisplatin, carboplatin, and oxaplatin); Plant    Alkaloids (including vincristine, Vinblastine, Vindesine,    Vinorelbine, paclitaxel, and Docetaxol); DNA Topoisomerase    Inhibitors (including etoposide, Teniposide, Topotecan,    9-aminocamptothecin, campto irinotecan, and crisnatol); mytomycin C;    Anti-metabolites; Anti-folates (including methotrexate,    Trimetrexate, mycophenolic acid, Tiazofurin, Ribavirin, EICAR,    hydroxyurea, deferoxamine); Pyrimidine analogs (including    5-Fluorouracil, Floxuridine, Doxifluridine, Ratitrexed,    capecitabine, cytarabine (ara C), Cytosine arabinoside, and    fludarabine); Purine analogs (including mercaptopurine and    Thioguanine); Hormonal therapies; Receptor antagonists (including    Tamoxifen, Raloxifene, megestrol, goscrclin, Leuprolide acetate,    flutamide, and bicalutamide); Retinoids/Deltoids (including EB 1089,    CB1093, KH 1060, vertoporfin (BPD-MA), Phthalocyanine,    photosensitizer Pc4, Demethoxy-hypocrellin A, (2BA-2-DMHA),    Interferon α, Interferon γ, Tumor necrosis factor); and others    (including Lovastatin, 1-methyl-4-phenylpyridinium ion,    staurosporine, Actinomycin D, Dactinomycin, bleomycin A2, Bleomycin    B2, Peplomycin, daunorubicin, Doxorubicin (adriamycin), Idarubicin,    Epirubicin, Pirarubicin, Zorubicin, Mitoxantrone, verapamil,    thapsigargin, Avastin, Erbitux, Rituxan, Prednisilone, Imatinib,    Thalidomide, Lenalidomide, Bortezomib, Gemcitabine, Erlotinib,    Gefitinib, Sorafenib, and Sutinib).

The chemotherapeutic agent and/or radiation therapy can be administeredaccording to therapeutic protocols well known in the art. It will beapparent to those skilled in the art that the administration of thechemotherapeutic agent and/or radiation therapy can be varied dependingon the disease being treated and the known effects of thechemotherapeutic agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent or radiation) on thepatient, and in view of the observed responses of the disease to theadministered therapeutic agents.

The heterocyclic compounds of the invention can be administered to apatient in the form of a pharmaceutical composition. The pharmaceuticalcomposition comprises one or more of the heterocyclic compounds of theinvention and one or more pharmaceutically acceptable excipients. Incertain instances, the pharmaceutical composition comprises one or moreheterocyclic compounds of the invention, one or more chemotherapeuticagents, and one or more pharamaceutically acceptable excipients.

In general, compounds of the present invention and the chemotherapeuticagent do not have to be administered in the same pharmaceuticalcomposition, and may, because of different physical and chemicalcharacteristics, have to be administered by different routes. Forexample, compounds of the present invention may be administeredintravenously to generate and maintain good blood levels, while thechemotherapeutic agent may be administered orally. The determination ofthe mode of administration and the advisability of administration, wherepossible, in the same pharmaceutical composition, is well within theknowledge of the skilled clinician. The initial administration can bemade according to established protocols known in the art, and then,based upon the observed effects, the dosage, modes of administration andtimes of administration can be modified by the skilled clinician.

The particular choice of chemotherapeutic agent or radiation will dependupon the diagnosis of the attending physicians and their judgment of thecondition of the patient and the appropriate treatment protocol.

A compound of the present invention, and chemotherapeutic agent and/orradiation may be administered concurrently (e.g., simultaneously,essentially simultaneously or within the same treatment protocol) orsequentially, depending upon the nature of the proliferative disease,the condition of the patient, and the actual choice of chemotherapeuticagent and/or radiation to be administered in conjunction (i.e., within asingle treatment protocol) with a compound of the present invention.

If a compound of the present invention, and the chemotherapeutic agentand/or radiation are not administered simultaneously or essentiallysimultaneously, then the optimum order of administration of the compoundof the present invention, and the chemotherapeutic agent and/orradiation, may be different for different tumors. Thus, in certainsituations the compound of the present invention may be administeredfirst followed by the administration of the chemotherapeutic agentand/or radiation; and in other situations the chemotherapeutic agentand/or radiation may be administered first followed by theadministration of a compound of the present invention. This alternateadministration may be repeated during a single treatment protocol. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the disease being treated and thecondition of the patient. For example, the chemotherapeutic agent and/orradiation may be administered first, especially if it is a cytotoxicagent, and then the treatment continued with the administration of acompound of the present invention followed, where determinedadvantageous, by the administration of the chemotherapeutic agent and/orradiation, and so on until the treatment protocol is complete.

Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of a component(therapeutic agent, i.e., compound of the present invention,chemotherapeutic agent or radiation) of the treatment according to theindividual patient's needs, as the treatment proceeds.

Compounds of the Invention

One aspect of the present invention relates to a compound represented byformula 1:

or an unsaturated form thereof or a pharmaceutically acceptable saltthereof;wherein

-   Y is —C(R₁₀)₂—, —(C═O)—, —(C═S)—, or —C(═NR₁₀)—;-   X is —N(R₁₀)—, or a bond;-   m is 0, 1, 2, 3, 4, 5, or 6;    A is —S(O)—, —S(O)₂—,    or —C(A₁)(A₂)-;-   each of A₁ and A₂ is independently H, alkyl, alkenyl, alkynyl, aryl,    cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl,    —C(O)N(R₁₀)₂, —C(O)R₁₀, —CO₂R₁₀, —S(O)₂N(R₁₀)₂, —S(O)R₁₀,    —S(O)₂OR₁₀, —S(O)₂R₁₀; or has the formula 1a:    wherein independently for each occurrence of 1a;-   n is 1, 2, 3, 4, 5, or 6;-   R₁₅ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl,    —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀,    or —C(O)N(R₁₀)₂; or is a polycyclic ring containing 8-14 carbon    atoms, of which one, two or three ring atoms are independently S, O    or N;-   or A₁ and A₂ taken together form ═O or ═S; or A₁ and A₂ taken    together with the carbon to which they are attached form a 5 to 8    membered heterocyclyl, of which one or two ring atoms are    independently S, O or N;-   B is O, S, —(C═O)—, —(C═S)— or,    or has the formula 1b:    -   wherein    -   D is N or CR₁₀;    -   p is 0, 1, 2, 3, 4, or 5;    -   each of R₇ and R₈ is independently for each occurrence H, alkyl,        alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl,        cycloalkenyl, or heteroaryl; or R₇ and R₈ taken together form a        3-8 membered ring; or R₇ and R₈ taken together form a 4-8        membered ring;    -   R₉ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂,        —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀,        —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or        acylthio;-   R₁ has the formula 1c:    wherein    -   q is 1, 2, 3, 4, or 5;    -   r is 1, 2, 3, 4, or 5;    -   Ar¹ is a monocyclic or bicyclic aryl with 6-14 ring atoms; or a        monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which        one, two or three ring atoms are independently S, O or N; or Ar¹        is represented by formula 1d:

Wherein

-   -   s is 0, 1, 2, 3, or 4;    -   each of X² and X³ is independently for each occurrence H, alkyl,        alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl,        heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro,        halide, OR₁₁, —C(O)N(R₁₀)(R₁₁), —C(O)R₁₁, —CO₂R₁₁,        —S(O)₂N(R₁₀)(R₁₁), SR₁₁, —S(O)R₁₁, —S(O)₂OR₁₁, —S(O)₂R₁₁,        —C(═NR₁₀)N(R₁₀)(R₁₁), or —C(═NR₁₀)(R₁₁); or has the formula 1a;    -   Ar² is a monocyclic or bicyclic aryl with 6-14 ring atoms; or a        monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which        one, two or three ring atoms are independently S, O or N;    -   X¹ is a bond, —C(R₁₀)₂—, —S—, —(NR₁₀)—, or —O—;

-   R₂ is H, a branched or unbranched alkyl or alkenyl, cycloalkyl,    heterocyclyl, or bicycloalkyl; or has the formula 1a:

-   R₃ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂,    —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀, —OC(O)N(R₁₀)₂,    —C(O)N(R₁₀)₂, halide, nitrile, nitro, or acylthio;

-   each of R₄, R₅ and R₁₀ independently for each occurrence is H,    alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl,    bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 1a ;    or

-   any two instances of R₁₀ taken together form a 3-8 membered ring; or    R₄ and R₅ taken together form a 3-8 membered ring;

-   R₆ is H or alkyl;

-   R₁₁ is independently for each occurrence H, alkyl, alkenyl, alkynyl,    aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl,    heteroaryl, or —[C(R₁₂)(R₁₃)]₁—R₁₄;    wherein

-   t is 0, 1, 2, 3, 4, or 5;

-   each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl,    aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, or heteroaralkyl; and

-   R₁₄ is independently for each occurence H, alkyl, aryl, heteroaryl,    heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

Another aspect of the invention relates to a compound having the formula10:

or an unsaturated form thereof or a pharmaceutically acceptable saltthereof;wherein

-   m represents independently for each occurrence 0, 1, 2, 3, 4, 5, or    6;-   A is —S(O)—, —S(O)₂—,    or —C(A₁)(A₂)-;-   each of A₁ and A₂ is independently H, alkyl, alkenyl, alkynyl, aryl,    cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl,    —C(O)N(R₁₀)₂, —C(O)R₁₀, —CO₂R₁₀, —S(O)₂N(R₁₀)₂, —S(O)R₁₀,    —S(O)₂OR₁₀, or —S(O)₂R₁₀; or has the formula 10a:

wherein independently for each occurrence of 10a;

-   -   n is 1, 2, 3, 4, 5, or 6; and    -   R₁₅ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl,        —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂,        —CO₂R₁₀, or —C(O)N(R₁₀)₂; or is a polycyclic ring containing        8-14 carbon atoms, of which one, two or three ring atoms are        independently S, O or N;

-   or A₁ and A₂ taken together form ═O or ═S; or A₁ and A₂ taken    together with the carbon to which they are attached form a 5 to 8    heterocyclyl, of which one or two ring atoms are independently S, O    or N

-   B is O, S, —(C═O)—, —(C═S)— or,    or has the formula 10b:    -   wherein    -   D is N or CR₁₀;    -   p is 0, 1, 2, 3, 4, or 5;    -   each of R₇ and R₈ is independently for each occurrence H, alkyl,        alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl,        cycloalkenyl, or heteroaryl; or R₇ and R₈ taken together form a        3-8 membered ring; or R₇ and R₈ taken together form a 4-8        membered ring;    -   R₉ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂,        —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀,        —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or        acylthio;

-   R₁ has the formula 10c or 10d:

wherein

-   -   q is 1, 2, 3, 4, or 5;    -   r is 1, 2, 3, 4, or 5;    -   W is a bond; or alkyl diradical, alkenyl diradical, or alkynyl        diradical;    -   Z is H, —SR₁₀, —S(O)₂R₁₁, —NR₁₀S(O)₂R₁₁, —S(O)R₁₀, —N(R₁₀)(R₁₁),        —C(O)R₁₁, —CO₂R₁₁, —C(O)N(R₁₀)(R₁₁), —C(S)N(R₁₀)(R₁₁),        —CH₂C(O)heterocyclyl, —NR₁₀C(O)R₁₁, —NR₁₀CO₂R₁₁,        —OC(O)N(R₁₀)(R₁₁), —NC(O)CH(R₁₀)(R₁₁), —C(═NR₁₀)N(R₁₀)(R₁₁),        —C(═NR₁₀)R₁₁, hydroxyalkyl, monocyclic aryl, bicyclic aryl,        heteroaryl, or heterocyclyl;    -   Ar¹ is a monocyclic or bicyclic aryl with 6-14 ring atoms; or a        monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which        one, two or three ring atoms are independently S, O or N; or Ar¹        is represented by formula 10e:    -   Wherein    -   s is 0, 1, 2, 3, or 4;    -   each of X² and X³is independently for each occurrence H, alkyl,        alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl,        heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro,        halide, OR₁₁, —C(O)N(R₁₀)(R₁₁), —C(O)R₁₁, —CO₂R₁₁,        —S(O)₂N(R₁₀)(R₁₁), SR₁₁, —S(O)R₁₁, —S(O)₂OR₁₁, —S(O)₂R₁₁,        —C(═NR₁₀)N(R₁₀)(R₁₁), or —C(═NR₁₀)(R₁₁); or has the formula 10a;    -   Ar² represent independently for each occurrence are monocyclic        or bicyclic aryl with 6-14 ring atoms; or a monocyclic or        bicyclic heteroaryl with 5-14 ring atoms, of which one, two or        three ring atoms are independently S, O or N;    -   X¹ is a bond, —C(R₁₀)₂—, —S—, —N(R₁₀)— or —O—;

-   R₂ is H, a branched or unbranched alkyl or alkenyl, cycloalkyl,    heterocyclyl, orbicycloalkyl; or has the formula 10a:

-   R₃ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂,    —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀, —OC(O)N(R₁₀)₂,    —C(O)N(R₁₀)₂, halide, nitrile, nitro, or acylthio;

-   each of R₄, R₅ and R₁₀ is independently for each occurrence H,    alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl,    bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 10a;

-   or any two instances of R₁₀ taken together form a 3-8 membered ring;    or R₄ and R₅ taken together form a 3-8 membered ring;

-   R₆ is H or alkyl;

-   R₁₁ is independently for each occurrence H, alkyl, alkenyl, alkynyl,    aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl,    heteroaryl, or —[C(R₁₂)(R₁₃)]₁—R₁₄;    wherein

-   t is0, 1, 2, 3, 4, or 5;

-   each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl,    aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, or heteroaralkyl; and

-   R₁₄ is independently for each occurrence H, alkyl, aryl, heteroaryl,    heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

Another aspect of the invention relates to a compound represented byformula 14:

or an unsaturated form thereof or a pharmaceutically acceptable saltthereof;wherein

-   Y is —C(R₁₀)₂—, —(C═O)—, —(C═S)—, or —C(═NR₁₀)—;-   X is —N(R₁₀)—, or a bond;-   m represents independently for each occurrence 0, 1, 2, 3, 4, 5, or    6;-   A is —S(O)—, —S(O)₂—,    or —C(A₁)(A₂)-;-   each of A₁ and A₂ is independently for each occurrence H, alkyl,    alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl,    heteroaryl, heteroaralkyl, —C(O)N(R₁₀)₂, —C(O)R₁₀, —CO₂R₁₀,    —S(O)₂N(R₁₀)₂, —S(O)R₁₀, —S(O)₂OR₁₀, —S(O)₂R₁₀; or has the formula    14a:    -   wherein independently for each occurrence of 14a;    -   n is 1, 2, 3, 4, 5, or 6; and    -   R₁₅ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl,        —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂,        —CO₂R₁₀, or —C(O)N(R₁₀)₂; or is a polycyclic ring containing        8-14 carbon atoms, of which one, two or three ring atoms are        independently S, O or N;-   or A₁ and A₂ taken together form ═O or ═S; or A₁ and A₂ taken    together with the carbon to which they are attached form a 5 to 8    heterocyclyl, of which one or two ring atoms are independently S, O    or N;-   B is —(C(R)₂X)—, —(XC(R)₂)—, or —(C(R)₂)₂—;-   X independently for each occurrence is S, —(NR₁₀)—, or —O—;-   R independently for each occurrence is H, alkyl, alkenyl, alkynyl,    aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, or    heteroaralkyl; or has formula 14a;-   R₁ has the formula 14b:

wherein

-   -   q is 1, 2, 3, 4, or 5;    -   r is 0, 1, 2, 3, 4, or 5;    -   Ar¹ is a monocyclic or bicyclic aryl with 6-14 ring atoms; or a        monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which        one, two or three ring atoms are independently S, O or N; or Ar¹        is represented by formula 14c:    -   Wherein    -   s is 0, 1, 2, 3, or 4;    -   each of X² and X³ is independently for each occurrence H, alkyl,        alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl,        heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro,        halide, —OR₁₁, —C(O)N(R₁₀)(R₁₁), —C(O)R₁₁, —CO₂R₁₁,        —S(O)₂N(R₁₀)(R₁₁), —SR₁₁, —S(O)R₁₁, —S(O)₂OR₁₁, —S(O)₂R₁₁,        —C(═NR₁₀)N(R₁₀)(R₁₁), or —C(═NR₁₀)(R₁₁); or has the formula 14a;    -   Ar² represent independently for each occurrence are monocyclic        or bicyclic aryl with 6-14 ring atoms; or a monocyclic or        bicyclic heteroaryl with 5-14 ring atoms, of which one, two or        three ring atoms are independently S, O or N;    -   X¹ is a bond, —(C(R₁₀)₂)—, —S—, —(NR₁₀)—, or —O—;

-   R₂ is H, a branched or unbranched alkyl or alkenyl, cycloalkyl,    heterocyclyl, or bicycloalkyl; or has the formula 14a:

-   R₃ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂,    —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀, —OC(O)N(R₁₀)₂,    —C(O)N(R₁₀)₂, halide, nitrile, nitro, or acylthio;

-   each of R₄, R₅ and R₁₀ is independently for each occurrence H,    alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl,    bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 14a;

-   or any two instances of R₁₀ taken together form a 3-8 membered ring;    or R₄ and R₅ taken together form a 3-8 membered ring;

-   R₆ is H or alkyl;

-   R₁₁ independently for each occurrence is H, alkyl, alkenyl, alkynyl,    aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl,    heteroaryl, or —[C(R₁₂)(R₁₃)]₁—R₁₄;    wherein

-   t is 0, 1, 2, 3, 4, or 5;

-   each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl,    aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, or heteroaralkyl; and

-   R₁₄ is independently for each occurrence H, alkyl, aryl, heteroaryl,    heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

The compounds described above may have one or more of the followingfeatures (where applicable):

-   Ar²(X²)_(r) is represented by the formula 3:    wherein-   R₁₈ is alkyl, alkenyl, halide, nitro, or amino;-   each of R₂₀ and R₂₁ is independently H, alkyl, aralkyl,    heteroaralkyl, alkoxy, or-   —[C(R₂₂)(R₂₃)]₁—R₂₄;-   t is independently for each occurrence 0, 1, 2, 3, 4, or 5;-   each of R₂₂ and R₂₃ is independently for each occurrence H, alkyl,    aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, or heteroaralkyl; and-   R₂₄ is independently for each occurrence H, alkyl, aryl, heteroaryl,    heterocyclylalkyl, alkoxy, amino, amido, or carboxyl; Y is —(C═O)—    and X is —NH—; B has the formula 6a or 6b:    wherein-   p is 0, 1, or 2;-   each of R₇ and R₈ independently for each occurrence is H or alkyl;    and-   R₉ is H, —OR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂,    —OCO₂R₁₀, or —OC(O)N(R₁₀)₂; B is S; A₁ and A₂ taken together form ═O    and B has the formula 8:    wherein-   p is 0, 1 or 2;-   each of R₇ and R₈ independently for each occurrence is H or alkyl;    and-   R₉ is H, —OR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂,    —OCO₂R₁₀, or —OC(O)N(R₁₀)₂;-   A₁ and A₂ are each H; R₁ has the formula 11:    wherein-   s is 0, 1, 2, 3, or 4;-   each of X³ is independently for each occurrence H or halide;-   each of R₁₈ and R₁₉ is independently H, alkyl, alkenyl, alkynyl,    aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl,    heteroaryl, or —[C(R₁₂)(R₁₃)]₁—R₁₄;    wherein-   t is 1, 2, 3, 4, or 5;-   each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl,    aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, or heteroaralkyl; and-   R₁₄ is independently for each occurrence H, alkyl, aryl, heteroaryl,    heterocyclylalkyl, alkoxy, amino, amido, or carboxyl; B has the    formula 12a or 12b:    wherein-   p is 0, 1, 2, 3, or 4;-   each of R₇ and R₈ is independently for each occurrence H or alkyl;    and-   R₉ is H, —OR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂,    —OCO₂R₁₀, or —OC(O)N(R₁₀)₂;-   wherein A is —C(A₁)(A₂)-; A₁ and A₂ taken together form ═O and B has    the formula 13:    wherein-   p is 0, 1, 2, 3, or 4;-   each of R₇ and R₈ independently for each occurrence is H or alkyl;    and-   R₉ is H, —OR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂,    —OCO₂R₁₀, or —OC(O)N(R₁₀)₂;-   and R₂ is bicycloalkyl.

The compound may have the structure 2:

wherein

-   Y is —C(R₁₀)₂—, —(C═O)—, or —(C═S)—;-   X is —N(R₁₀)—;-   m is 0, 1, 2, or 3;-   r is 1, 2, 3, 4, or 5;-   s is 0, 1, 2, 3, or 4;-   A is —S(O)—, —S(O)₂—,    or —C(A₁)(A₂)-;-   each of A₁ and A₂ is independently H, alkyl, aryl, cycloalkyl,    aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R₁₀)₂,    —C(O)R₁₀, —CO₂R₁₀, —S(O)₂N(R₁₀)₂, —S(O)R₁₀, —S(O)₂OR₁₀, or    —S(O)₂R₁₀; or has the formula 2a:    -   wherein independently for each occurrence of 2a;    -   n is 1, 2, 3, 4, 5, or 6;    -   R₁₅ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl,        —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂,        —CO₂R₁₀, or —C(O)N(R₁₀)₂; or is a polycyclic ring containing        8-14 carbon atoms, of which one, two or three ring atoms are        independently S, O or N;-   or A₁ and A₂ taken together form ═O or ═S;-   B is —(C═O)—, —(C═S)—, O, or S; or has the formula 2b:    -   wherein    -   D is N or CR₁₀;    -   p is 0, 1, 2, or 3;    -   each of R₇ and R₈ is independently for each occurrence H, alkyl,        alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl,        cycloalkenyl, or heteroaryl; or R₇ and R₈ taken together form a        3-8 membered ring; or R₇ and R₈ taken together form a 4-8        membered ring;    -   R₉ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂,        —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀,        —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or        acylthio;-   Ar² is a monocyclic or bicyclic aryl with 6-10 ring atoms; or a    monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which    one, two or three ring atoms are independently S, O or N;-   X² is independently for each occurrence H, alkyl, alkenyl, alkynyl,    aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl,    hydroxyl, acyloxy, nitrile, nitro, halide, OR₁₁, —C(O)N(R₁₀)(R₁₁),    —C(O)R₁₁, —CO₂R₁₁, —S(O)₂N(R₁₀)(R₁₁), SR₁₁, —S(O)R₁₁, —S(O)₂OR₁₁,    —S(O)₂R₁₁, —C(═NR₁₀)N(R₁₀)(R₁₁), or —C(═NR₁₀)(R₁₁); or has the    formula 2a;-   each of R₄, R₅ and R₁₀ is independently for each occurrence H,    alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl,    bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 2a ;    or-   any two instances of R₁₀ taken together form a 3-8 membered ring; or    R₄ and R₅ taken together form a 3-8 membered ring;-   X³ is independently for each occurrence H, alkyl, alkenyl, —OR₁₁, or    halide; or has formula 2a;-   each of R and R′ is independently for each occurrence H or alkyl;-   R₆ is H or alkyl;-   R₁₁ is independently for each occurrence H, alkyl, alkenyl, alkynyl,    aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl,    heteroaryl, or —[C(R₁₂)(R₁₃)]₁—R₁₄;    wherein-   t is independently for each occurrence 0, 1, 2, 3, 4, or 5;-   each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl,    aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, or heteroaralkyl; and-   R₁₄ is independently for each occurrence H, alkyl, aryl, heteroaryl,    heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

Alternatively, the compound may have the formula 4

wherein

-   Y is —C(R₁₀)₂—, —(C═O)—, or —(C═S)—;-   X is —N(R₁₀)—;-   m is 0, 1, 2, 3, or 4;-   s is 0, 1, 2, 3;-   each of A₁ and A₂ is independently H, alkyl, aryl, cycloalkyl,    aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R₁₀)₂,    —C(O)R₁₀, —CO₂R₁₀, —S(O)₂N(R₁₀)₂, —S(O)R₁₀, —S(O)₂OR₁₀, or    —S(O)₂R₁₀; or has the formula 4a:    -   wherein independently for each occurrence of 4a;    -   n is 1, 2, 3, 4, 5, or 6; and    -   R₁₅ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl,        —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂,        —CO₂R₁₀, or —C(O)N(R₁₀)₂; or is a polycyclic ring containing        8-14 carbon atoms, of which one, two or three ring atoms are        independently S, O or N;-   or A₁ and A₂ taken together form ═O or ═S;-   B is O, S, —(C═O)—, or —(C═S)—; or has the formula 4b:    -   wherein    -   D is N or CR₁₀;    -   p is 0, 1, 2, 3;    -   each of R₇ and R₈ is independently for each occurrence H, alkyl,        alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl,        cycloalkenyl, or heteroaryl; or R₇ and R₈ taken together form a        3-8 membered ring; or R₇ and R₈ taken together form a 4-8        membered ring;    -   R₉ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂,        —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀,        —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or        acylthio;-   R₆ is H or alkyl;-   each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl,    aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, or heteroaralkyl;-   R₁₄ is independently for each occurrence H, alkyl, aryl, heteroaryl,    heterocyclylalkyl, alkoxy, amino, amido, or carboxyl;-   R₁₆ is H, alkyl, alkenyl, or OR₁₁; has the formula 4a;-   each of X³ independently for each occurrence is H or halide;-   R₁₈ is alkyl, alkenyl, halide, nitro, or amino;-   each of R₂₀ and R₂₁ is independently H, alkyl, aralkyl,    heteroaralkyl, alkoxy, or-   —[C(R₂₂)(R₂₃)]₁—R₂₄;-   t is independently for each occurrence 1, 2, 3, 4, or 5;-   each of R₂₂ and R₂₃ is independently for each occurrence H, alkyl,    aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, or heteroaralkyl; and-   R₂₄ is independently for each occurrence H, alkyl, aryl, heteroaryl,    heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

Specific compounds include those shown below:

Methods of the Invention

One aspect of the present invention relates to a method of treating aBcl-mediated disorder, comprising the step of: administering to apatient in need thereof a therapeutically effective amount of a compoundof formula 1, 10, or 14, or a salt thereof as described above. Inanother aspect, the present invention relates to a method of treating aBcl-mediated disorder, comprising the step of: administering to apatient in need thereof a therapeutically effective amount of achemotherapeutic agent in combination with a therapeutically effectiveamount of a compound of compound of formula 1, 10, or 14, or a saltthereof as described above.

In certain embodiments of either aspect, the Bcl-mediated disorder iscancer or neoplastic disease. The cancer or neoplastic disease can beselected from the group consisting of acute leukemia, acute lymphocyticleukemia, acute myelocytic leukemia, myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic lymphocytic leukemia,polycythemia Vera, Hodgkin's disease, non-Hodgkin's disease; multiplemyeloma, Waldenstrom's macroglobulinemia, heavy chain disease,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,stadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterinecancer, testicular tumor, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, retinoblastoma, and endometrial cancer.

The cancer can also be follicular lymphoma, diffuse large B-celllymphoma, mantle cell lymphoma, chronic lymphocytic leukemia prostratecancer, breast cancer, neuroblastoma, colorectal, endometrial, ovarian,lung cancer, hepatocellular carcinoma, multiple myeloma, head and neckor testicular cancer.

In certain embodiments, the cancer over-expresses a Bcl protein and/oris dependent upon a Bcl protein for growth and survival. The Bcl proteincan be, e.g., Bcl-2 or Bcl-xL. In other embodiments, the cancer exhibitsa t(14;18) chromosomal translocation.

The compound can be administered parenterally, intramuscularly,intravenously, subcutaneously, orally, pulmonary, intrathecally,topically or intranasally. In certain embodiments, the compound isadministered systemically. In certain embodiments, the patient is amammal, preferably a primate, more preferably a human.

Pharmaceutical Compositions

In another aspect, the present invention provides pharmaceuticallyacceptable compositions which comprise a therapeutically-effectiveamount of one or more of the compounds described above, formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) oral administration, for example,drenches (aqueous or non-aqueous solutions or suspensions), tablets,e.g., those targeted for buccal, sublingual, and systemic absorption,boluses, powders, granules, pastes for application to the tongue; (2)parenteral administration, for example, by subcutaneous, intramuscular,intravenous or epidural injection as, for example, a sterile solution orsuspension, or sustained-release formulation; (3) topical application,for example, as a cream, ointment, or a controlled-release patch orspray applied to the skin; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; (5) sublingually; (6) ocularly;(7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which maybe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which may be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred per cent, this amount will range fromabout 0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges, powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles, and/or as mouth washes and the like,each containing a predetermined amount of a compound of the presentinvention as an active ingredient.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which may be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which may be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease may be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required. The ointments, pastes, creams and gels may contain, inaddition to an active compound of this invention, excipients, such asanimal and vegetable fats, oils, waxes, paraffins, starch, tragacanth,cellulose derivatives, polyethylene glycols, silicones, bentonites,silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms may be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux may be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they may be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Exemplification

The invention now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

EXAMPLE 1

To a solution of phenol 2 (750 mg, 3 mmol, 1 eq) in DMF (5 mL) at 0° C.was added NaH (130 m g, 3.6 mmol, 1.2 eq) followed by MeI (280 μL, 4.5mmol, 1.5 eq). The reaction mixture was stirred at rt for 24 h and thenquenched with water. The mixture was diluted with EtOAc and washed withwater (twice) then brine. The solution was dried over MgSO₄, filteredand concentrated to afford 795 mg (100%) of crude product 3.Part B

Aldehyde 3 (795 mg, 3.03 mmol, 1 eq) and hydroxylamine hydrochloride(253 mg, 3.64 mmol, 1.2 eq) were dissolved in THF/MeOH (3:2, 10mL).Water (2 mL) was added and the pH was adjusted to 9 with 6.0 N KOH. Thereaction mixture was stirred at rt overnight. After 16 h, sodiumcyanoborohydride (381 mg, 6.07 mmol, 2 eq) was added followed by acrystal of methyl orange. The pH was adjusted to 2 and the resultingruby red color was maintained for the duration of the reaction by thefrequent addition of 1 N HCl. After stirring for 2 h another portion ofsodium cyanoborohydride (381 mg) was added. After stirring for a totalof 16 h, the pH of the reaction mixture was brought to 7 and DCM wasadded. The mixture was washed with water (three times), brine and thendried over MgSO₄. The crude product was purified by flash chromatography(50% EtOAc in hexanes then 100% EtOAc) to afford 706 mg (83%) ofhydroxylamine 4.Part C

A solution of hydroxylamine 4 (705 mg, 2.53 mmol, 1 eq) and methylglyoxylate (445 mg, 5.05 mmol, 2 eq) in benzene (15 mL) was heated atreflux with a Dean Stark trap overnight. Excess solvent was removedunder reduced pressure and the resulting nitrone 5 was taken on crude inthe next step.Part D

Nitrone 5 (882 mg, 2.53 mmol, 1 eq), allylic alcohol 6 (U.S. Ser. No.,Ser. No. 11/156,364, filed Jun. 17, 2005) (820 mg, 3.79 mmol, 1.5 eq)and Ti(iOPr)₄ (1.12 mL, 3.79 mmol, 1.5 eq) were dissolved in toluene (5mL) and heated in the microwave at 120° C. for 10 min The reactionmixture was diluted with EtOAc (15 mL) and3-(dimethylamino)-1,2-propanediol (500 μL) was added. After stirring for2 h, EtOAc was added and the mixture was washed with water (three times)then brine, dried over MgSO₄, filtered over Celite and concentrated. Thecrude residue was purified by flash chromatography (5:1 hexanes/EtOAc)to afford 575 mg (43%) of lactone 7.Part E

To a solution of 7 (225 mg, 0.042 mmol, 1 eq) in THF (6 mL) was addedpyridine (2 mL) and HF/pyridine (2 mL). The mixture was stirred at rtfor 4 h then TMSOMe (8 mL) was added. Solvent was removed under reducedpressure and the crude product was purified by flash chromatography(EtOAc) to afford 128 mg (72%) of 8 as a white foam.Part F

To a 0° C. solution of lactone 8 (0.94 g, 2.2 mmol, 1 eq) in DCM (22 mL)was added triethylamine (0.68 mL, 4.9 mmol, 2.2 eq) followed by thedropwise addition of methanesulfonyl chloride (0.38 mL, 4.9 mmol, 2.2eq). The reaction mixture was allowed to warm to rt over 12 h, afterwhich TLC and LC/MS confirmed complete consumption of alcohol. Themixture was then poured into DCM (100 mL) and a saturated sodiumbicarbonate solution (25 mL). The layers were separated and the aqueouslayer was extracted with DCM (3×30 mL). The combined organic extractswere dried (MgSO₄), filtered and concentrated in vacuo. The crudematerial was purified by gradient flash chromatography (100 g SiO₂,30-70% EtOAc/Hex) to afford 9 (1.04 g, 2.1 mmol, 94%).Part G

To neat mesylate 9 (450 mg, 0.91 mmol) at rt was added samarium iodide(27 mL of a 0.1 M THF solution, 2.7 mmol). After stirring at rt for 1 h,the reaction was quenched with a 5% ammonium chloride solution (10 mL)which resulted in an immediate color change of the reaction mixture fromdark blue to yellow. The reaction mixture was then filtered through apad of celite and the filtrate was diluted with water (100 mL) and EtOAc(100 mL). The aqueous layer was extracted with EtOAc (2×50 mL). Thecombined organic extracts were washed with brine (50 mL), dried (MgSO₄),filtered and concentrated in vacuo. The crude material was purified bygradient flash chromatography (75 g SiO₂, 30-80% EtOAc/Hex) to afford 10(190 mg, 2.1 mmol, 52% yield).Part H

To a rt solution of (+)-isopinocampheylamine 11 (0.25 mL, 1.5 mmol) inDCM (2 mL) was added AlMe₃ (0.71 mL of a 2 M solution in hexane, 1.4mmol). After stirring for 10 min, a solution of lactone 10 (190 mg, 0.47mmol) in DCM (3 mL) was added and the mixture was stirred at rt. Afterstirring for 16 h, the reaction was quenched with a saturated aqueousRochelle Salt solution (5 mL) and vigorously stirred at 23° C. for 2 huntil a clear biphasic mixture appeared. The aqueous layer was separatedand extracted with DCM (2×25 mL). The combined organic extracts werewashed with brine (10 mL), dried (MgSO₄), filtered and concentrated invacuo. The crude material was purified by gradient flash chromatography(50 g SiO₂, 2-5% MeOH/DCM) to afford 201 mg (77%) of 12 as a yellow oil.Part I

To a degassed (Ar) solution of pyrrolidine 12 (190 mg, 0.34 mmol) in aTHF/H₂O mixture (1:1, 4 mL) was added boronic acid 13 (120 mg, 0.68mmol), palladium acetate (12 mg, 0.05 mmol), potassium carbonate (190mg, 1.4 mmol) and finally phosphine ligand (Anderson, K. W.; et. al.,Angew. Chemie 2005, 44, 2922) (54 mg, 0.1 mmol). The reaction was heatedto 65° C. After 4 h at 65° C., the reaction mixture was allowed to coolto 23° C. over the course of an hour, diluted with DCM and filteredthrough a pad of sand and celite. The filtrate was. then extracted usingDCM (50 mL) from a pH 4 water solution (20 mL). The aqueous layer wasseparated and extracted with DCM (2×20 mL), the combined organicextracts were washed with brine (15 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The crude residue was used in the subsequentreaction without further purification.Part J

To a solution of crude pyrrolidine 15 (190 mg, 0.34 mmol) in MeOH (4 mL)was added formaldehyde (41 uL of a 37% aqueous solution, 1.37 mmol)followed by sodium cyanoborohydride (43 mg, 0.68 mmol) in a singleportion. After stirring for 12 h at 23° C., the reaction solution wasconcentrated in vacuo. The crude material was purified by gradient-flashchromatography (75 g SiO₂, 2-10% MeOH/DCM) to afford 130 mg (64% over 2steps) of 16 as a white solid.Part K

To a solution of pyrrolidine 17 (11 mg, 0.02 mmol) in THF/DMF (4:1, 1mL). was added HBTU (10 mg, 0.04 mmol) followed by the addition ofphenethylamine (5 uL, 0.04 mmol). After stirring at 23° C. for 1 h, thereaction mixture was diluted with methanol (0.5 mL) and purifieddirectly on a prep reverse phase HPLC, using aqueous 40 mM ammoniumbicarbonate/acetonitrile gradient as eluent to yield 5 mg (40%) of 1. MS(ESI(+)) m/z 697.3. (M+H)⁺.

EXAMPLE 2

Part A

Under argon atmosphere, aryl bromide 3 (2.32 mmol), boronic acid 14 (2.8mmol), phosphine ligand (0.1 mmol), palladium acetate (0.5 mmol), andpotassium carbonate (9.3 mmol) were suspended in degassed water andheated with stirring at 60° C. for 8 h (K. W. Anderson and S. L.Buchwald, Ang. Chem. Int. Ed., 2005, 44, 2). The mixture was poured intoDCM (40 mL) and water (20 mL), and the pH of the aqueous layer wasadjusted to 3 with 2N HCl. The layers were mixed and separated, and theaqueous layer was extracted with DCM (20 mL). The organic layers werecombined, washed with saturated aqueous NaCl, dried over sodium sulfate,and concentrated to a light yellow oil. Purification by silica gelchromatography (0.5% HOAc/20-40% ethyl acetate/hexanes) yielded paleyellow solid (33% yield).Part B

The biphenyl acid 15 (0.76 mmol) and (S)-diamine 16 (1.1 mmol) weredissolved in THF/water (10 mL, 4:1) and treated with HOBt (0.9 mmol) andEDC-HCl (0.9 mmol). After stirring 12 h at 23° C., the mixture waspoured into ethyl acetate (30 mL) and water (15 mL). The organic layerwas washed with 5% NaHCO₃, saturated aqueous NaCl, and then dried oversodium sulfate, and concentrated. The residue was purified by silica gelchromatography (0.5% NE₄OH/2-8% MeOH/DCM) to give a pale yellow oil (65%yield).Part C

Boc-L-proline 18 (0.46 mmol) and (+)-isopinocamphylamine (0.46 mmol)with diisopropylethylamine are dissolved in DMF (2 mL) and DCM (1 mL)and treated with HBTU (0.46 mmol). The mixture is stirred at 23° C. for12 h and then poured into ether (40 mL) and water (20 mL). The organiclayer is washed with additional water (20 mL), 5% NaHCO₃, 1N HCl,saturated aqueous NaCl, and then dried over MgSO₄. The oil produced fromconcentration is restored in ether (5 mL) and stirred with HCl indioxane (4 N, 5 mL) for 4 h. The solution is concentrated in vacuo anddried to produce a white solid. (80% yield)Part D

The amine 19 (0.16 mmol) and aldehyde 17 (0.54 mmol) were dissolved inmethanol (1.2 mL) and treated with acetic acid (0.05 mL) and sodiumcyanoborohydride (0.16 mmol). After stirring for 12 h, the product waspurified using reverse-phase HPLC (MeCN/0.1% NH₄HCO₃ in water) andlyophilized to give a white solid (6.2 mg). MS (ESI(+)) m/z 696.4(M+H)⁺.

EXAMPLE 3

Compound 18 was synthesized according to the procedure described inExample 2, using Boc-D-proline in place of Boc-L-proline. MS (ESI(+))m/z 696.4 (M+H)+.

EXAMPLE 4

Compound 19 was synthesized according to the procedure described inExample 2, using hydroxy-Boc-L-proline in place of Boc-L-proline.

EXAMPLE 5

Compound 20 was synthesized according to the procedure described inExample 1, using N,N-dimethylamino ethyl amine in place ofphenethylamine. 70% overall yield. Parent MS (ESI(+)) m/z 664.16 (M+H)+,Major ion fragment m/z 332.56 (M+2H/2)+

EXAMPLE 6

Compound 21 was synthesized according to the procedure described inExample 1, using (S)—N′N′-4-trimethylpentane-1,2-diamine in place ofphenethylamine. 70% overall yield. Parent MS (ESI(+)) m/z 720.25 (M+H)+,major ion fragment m/z 360.52 (M+2H/2)+.

EXAMPLE 7

Compound 22 was synthesized according to the procedure described inExample 1, using (S)—N′N′-dimethyl-3-phenylpropane-1,2-in place ofphenethylamine. 70% overall yield. Parent MS (ESI(+)) m/z 754.23 (M+H)+,major ion fragment m/z 377.59 (M+2H/2).

EXAMPLE 8

Compound 22 was synthesized according to the procedure described inExample 1, using 1-ethyl-(S)-2-Pyrrolidinemethanamine in place ofphenethylamine. 70% overall yield. Parent MS (ESI(+)) m/z 704.3 (M+H)+,major ion fragment m/z 352.65 (M+2H/2).

EXAMPLE 9

Under an argon atmosphere compound 25 (synthesized according toprocedure described in Example 1, compound 12) (100 mg),4-(dimethylaminocarbonyl)phenylboronic acid (71 mg), Cs₂CO₃ (120 mg),KOAc (20 mg), and Pd(dppf)Cl₂ (10 mg) were suspended in DMSO (6 mL) andheated at 60° C. during 3 h. Additional Pd(dppf)Cl₂ (5 mg) was added tothe reaction mixture after 2.5 h. The reaction mixture was then cooledto rt and diluted with DCM (25 mL) and then extracted with aqueoussolution of NaS₂CNMe₂ (8 mL). The aqueous layer was separated andextracted with DCM (3×25 mL). The combined organics were washed withwater (25 mL) and brine (25 mL), dried on Na₂SO₄, and concentrated underreduced pressure. The crude material was purified using silica gelcolumn chromatography to yield the desired product.

EXAMPLE 10

Part A

Boc-L-3-trans-hydroxyproline 27 (250 mg, 1.08 mmol, 1.0 eq) and(+)-isopinocamphylamine (166 mg, 1.08 mmol, 1.0 eq) withdiisopropylethylamine (280 mg, 2.16 mmol, 2.0 eq) were dissolved in DCM(5 mL) and treated with HBTU (492.0 mg, 1.3 mmol, 1.2 eq). The mixturewas stirred at rt for 12 h and then poured into diethylether (40 mL) andwater (20 mL). The organic layer was washed sequentially with additionalwater (20 mL), 5% sodium bicarbonate, 1 M hydrochloric acid, saturatedaqueous sodium chloride, and then dried over sodium sulfate. The oilproduced from concentration was restored in diethylether (5 mL) andstirred with hydrochloric acid in dioxane (4 M, 5 mL) for 4 h. Thesolution was concentrated in vacuo and dried to produce 3 as a whitesolid. 80% yield.Part B

To a degassed solution of iodide 29 (1.0 g, 3.8 mmol, 1.0 eq) andboronic acid 5 (1.37 g, 7.6 mmol, 2.0 eq) in a THF/water mixture (1:5,18 mL) was added palladium acetate (22 mg, 0.09 mmol, 0.025 eq),potassium carbonate (2.1 g, 15 mmol, 4 eq) and finally a sulfated S-Phosligand (100 mg, 0.19 mmol, 0.050 eq) (Anderson, K. W.; et. al., Angew.Chemie 2005, 44, 2922). Under an argon atmosphere, the clear mixture washeated at 65° C. for 2 h with vigorous stirring. The reaction mixturewas allowed to cool to rt and was then diluted with THF (3 mL) andacetic acid (3 mL). To this stirring mixture was added formalin solution(2.4 mL, 30 mmol, 8.0 eq) and sodium cyanoborohydride (710.0 mg, 11mmol, 3.0 eq). After stirring for 15 min, the mixture was diluted withwater (50 mL) and extracted twice with EtOAc (2×75 mL). The combinedorganic layers were washed with saturated aqueous sodium chloride (30mL) and dried over sodium sulfate. Concentration in vacuo provided apale yellow oil of 30 that was used in the subsequent reaction withoutfurther purification.

The yellow oil 30 from the previous step (3.8 mmol, 1.0 eq) with diamine7 (810 mg, 4.5 mmol, 1.2 eq) and diisopropylethylamine (2.0 mL, 11 mmol,3.0 eq) was dissolved in DCM (10 mL) and treated with HBTU (1.7 g, 4.5mmol, 1.2 eq) and stirred at rt for 2 h. The clear solution was mixedwith 5% aqueous sodium bicarbonate (50 mL) and extracted twice with DCM(2×50 mL). The combined organic extracts were washed with brine (25 mL),dried over sodium sulfate, and concentrated in vacuo. The crude mixturewas purified by silica gel chromatography (0.5% ammonium hydroxide/3-10%methanol/DCM) to afford a white foam of 31 (610 mg, 35% for threesteps). MS (ESI(+)) 462.4 m/z (M+H)⁺.

To a DCM solution (4 mL) of alcohol 31 (165 mg, 0.35 mmol, 1.0 eq) wasadded triethylamine (0.3 mL, 2.1 mmol, 6.0 eq) followed by Dess-Martinperiodinane (212 mg, 0.5 mmol, 1.4 eq). The reaction was stirred for 1.5h at rt and then diluted with DCM (30 mL). The organic mixture waswashed sequentially with 5% aqueous sodium thiosulfate, 5% sodiumbicarbonate, water, and brine (25 mL each) and dried over sodiumsulfate. Concentration in vacuo produced a light amber oil of 32 useddirectly in the next step. MS (ESI(+)) 460.4 m/z (M+H)⁺.Part C

The amine hydrochloride 28 (60.0 mg, 0.2 mmol, 3.0 eq) and aldehyde 32(30.0 mg, 0.065 mmol, 1.0 eq) were dissolved in methanol (1.2 mL) andtreated with triethylamine (20.0 mg, 0.2 mL, 3.0 eq) and sodiumtriacetoxyborohydride (55.0 mg, 0.26 mmol, 4.0 eq). After stirring for12 h, the product was purified using reverse-phase HPLC (MeCN/0.1%formic acid in water) and concentrated by lyophilization to give 26 as awhite powder (4.0 mg). MS (ESI(+)) 710.7 m/z (M+H)⁺.

EXAMPLE 11

Compound 33 was synthesized according to the procedure described inExample 10, using Boc-L-4-thiaproline in place ofBoc-L-3-trans-hydroxyproline. MS (ESI(+)) m/z 712.5 (M+H)+.

EXAMPLE 12

Compound 34 was synthesized according to the procedure described inExample 10, using Boc-L-3-dimethyl-4-thiaproline in place ofBoc-L-3-trans-hydroxyproline. MS (ESI(+)) m/z 740.5 (M+H)+.

EXAMPLE 13

Compound 35 was synthesized according to the procedure described inExample 10, using Boc-L-4-trans-Fmoc-aminoproline in place ofBoc-L-3-trans-hydroxyproline. Before final purification, the Fmoc groupwas removed by treatment with 15% piperdine in methanol. This methanolsolution was submitted directly to reverse-phase HPLC. MS (ESI(+)) m/z708.5 (M+H)+.

EXAMPLE 14

Compound 36 was synthesized according to the procedure described inExample 10, using Boc-L-4-cis-Fmoc-aminoproline in place ofBoc-L-3-trans-hydroxyproline. Before final purification, the Fmoc groupwas removed by treatment with 15% piperdine in methanol. This methanolsolution was submitted directly to reverse-phase HPLC. MS (ESI(+)) m/z708.5 (M+H)+.

EXAMPLE 15

Compound 37 was synthesized according to the procedure described inExample 10, using Boc-L-pipecolic acid in place ofBoc-L-3-trans-hydroxyproline. MS (ESI(+)) m/z 708.5 (M+H)+.

EXAMPLE 16

Compound 38 was synthesized according to the procedure described inExample 1, using Boc-S-2-morpholinecarboxylic acid in place ofBoc-L-3-trans-hydroxyproline. MS (ESI(+)) m/z 710.5 (M+H)+.

EXAMPLE 17

Bcl-2 binding affinity analysis data is presented below for variouscompounds of the invention. Note that “****” indicates that the Ki is<0.1 μM; “***” indicates that the Ki is 0.1-0.3 μM; “**” indicates thatthe Ki is 0.3-50 μM; and “*” indicates that the Ki is >50 μM. CompoundBcl Ki 1 **** 13 * 18 ** 23 **** 24 * 26 **** 33 **** 34 **** 35 **** 36**** 37 * 38 **

Incorporation by Reference

All of the U.S. patents, U.S. patent application publications, and PCTpatent application publications designating the U.S. that are citedherein are hereby incorporated by reference.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1. A compound represented by formula 1:

or an unsaturated form thereof or a pharmaceutically acceptable salt thereof; wherein Y is —C(R₁₀)₂—, —(C═O)—, —(C═S)—, or —C(═NR₁O)—; X is —N(R₁₀)—, or a bond; m is 0, 1, 2, 3, 4, 5, or 6; A is —S(O)—,

or —C(A₁)(A₂)-; each of A₁ and A₂ is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R₁₀)₂, —C(O)R₁₀, —CO₂R₁₀, —S(O)₂N(R₁₀)₂, —S(O)R₁₀, —S(O)₂OR₁₀, —S(O)₂R₁₀; or has the formula 1a:

wherein independently for each occurrence of 1a; n is 1, 2, 3, 4, 5, or 6; R₁₅ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, or —C(O)N(R₁₀)₂; or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N; or A₁ and A₂ taken together form ═O or ═S; or A₁ and A₂ taken together with the carbon to which they are attached form a 5 to 8 membered heterocyclyl, of which one or two ring atoms are independently S, O or N; B is O, S, —(C═O)—, —(C═S)— or,

or has the formula 1b:

wherein D is N or CR₁₀; p is 1, 2, 3, 4, or 5; each of R₇ and R₈ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heteroaryl; or R₇ and R₈ taken together form a 3-8 membered ring; or R₇ and R₈ taken together form a 4-8 membered ring; R₉ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀, —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or acylthio; R₁ has the formula 1c:

wherein q is 1, 2, 3, 4, or 5; r is 0, 1, 2, 3, 4, or 5; Ar¹ is a monocyclic or bicyclic aryl with 6-14 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N; or Ar¹ is represented by formula 1d:

Wherein s is 0, 1, 2, 3, or 4; each of X² and X³is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, OR₁₁, —C(O)N(R₁₀)(R₁₁), —C(O)R₁₁, —CO₂R₁₁, —S(O)₂N(R₁₀)(R₁₁), SR₁₁, —S(O)R₁₁, —S(O)₂OR₁i, —S(O)₂R₁₁, —C(═NR₁₀)N(R₁₀)(R₁₁), or —C(═NR₁₀)(R₁₁); or has the formula 1a; Ar² is a monocyclic or bicyclic aryl with 6-14 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N; X¹ is a bond, —C(R₁₀)₂—, —S—, -(NR₁₀)—, or —O—; R₂ is H, a branched or unbranched alkyl or alkenyl, cycloalkyl, heterocyclyl, or bicycloalkyl; or has the formula 1a: R₃ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀, —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or acylthio; each of R₄, R₅ and R₁₀ independently for each occurrence is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 1a ; or any two instances of R₁₀ taken together form a 3-8 membered ring; or R₄ and R₅ taken together form a 3-8 membered ring; R₆ is H or alkyl; R₁₁ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R₁₂)(R₁₃)]₁—R₁₄; wherein t is 1, 2, 3, 4, or 5; each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and R₁₄ is independently for each occurence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.
 2. The compound of claim 1, wherein the compound has the structure 2:

wherein Y is —C(R₁₀)₂—, —(C═O)—, or —(C═S)—; X is —N(R₁₀)—; m is 0, 1, 2, or 3; r is 1, 2, 3, 4, or 5; s is 0, 1, 2, 3, or 4; A is—S(O)—, —S(O)₂—,

or —C(A₁)(A₂)-; each of A₁ and A₂ is independently H, alkyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R₁₀)₂, —C(O)R₁₀, —CO₂R₁₀, —S(O)₂N(R₁₀)₂, —S(O)R₁₀, —S(O)₂OR₁₀, or —S(O)₂R₁₀; or has the formula 2a:

wherein independently for each occurrence of 2a; n is 1, 2, 3, 4, 5, or 6; R₁₅ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, or —C(O)N(R₁₀)₂; or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N; or A₁ and A₂ taken together form ═O or ═S; B is —(C═O)—, —(C═S)—, O, or S; or has the formula 2b:

wherein D is N or CR₁₀; p is 0, 1, 2, or 3; each of R₇ and R₈ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heteroaryl; or R₇ and R₈ taken together form a 3-8 membered ring; or R₇ and R₈ taken together form a 4-8 membered ring; R₉ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀, —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or acylthio; Ar² is a monocyclic or bicyclic aryl with 6-10 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N; X² is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, OR₁₁, —C(O)N(R₁₀)(R₁₁), —C(O)R₁₁, —CO₂R₁₁, —S(O)₂N(R₁₀)(R₁₁), SR₁₁, —S(O)R₁₁, —S(O)₂OR₁₁, —S(O)₂R₁₁, —C(═NR₁₀)N(R₁₀)(R₁₁), or —C(═NR₁₀)(R₁₁); or has the formula 2a; each of R₄, R₅ and R₁₀ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 2a; or any two instances of R₁₀ taken together form a 3-8 membered ring; or R₄ and R₅ taken together form a 3-8 membered ring; X³ is independently for each occurrence H, alkyl, alkenyl, —OR₁₁, or halide; or has formula 2a; each of R and R′ is independently for each occurrence H or alkyl; R₆ is H or alkyl; R₁₁ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R₁₂)(R₁₃)]₁—R₁₄; wherein t is independently for each occurrence 0, 1, 2, 3, 4, or 5; each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and R₁₄ is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.
 3. The compound of claim 2, wherein Ar²(X²)_(r) is represented by the formula 3:

wherein R₁₈ is alkyl alkenyl, halide, nitro, or amino; each of R₂₀ and R₂₁ is independently H, alkyl, aralkyl, heteroaralkyl, alkoxy, or —[C(R₂₂)(R₂₃)]₁—R₂₄; t is independently for each occurrence 0, 1, 2, 3, 4, or 5; each of R₂₂ and R₂₃ is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and R₂₄ is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.
 4. The compound of claim 1, wherein the compound has the formula 4

wherein Y is —C(R₁₀)₂—, —(C═O)—, or —(C═S)—; X is —N(R₁₀)—; m is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3; each of A₁ and A₂ is independently H, alkyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R₁₀)₂, —C(O)R₁₀, —CO₂R₁₀, —S(O)₂N(R₁₀)₂, —S(O)R₁₀, —S(O)₂OR₁₀, or —S(O)₂R₁₀; or has the formula 4a:

wherein independently for each occurrence of 4a; n is 1, 2, 3, 4, 5, or 6; and R₁₅ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, or —C(O)N(R₁₀)₂; or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N; or A₁ and A₂ taken together form ═O or ═S; B is O, S, —(C═O)—, or —(C═S)—; or has the formula 4b:

wherein D is N or CR₁₀; p is 0, 1, 2, 3; each of R₇ and R₈ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heteroaryl; or R₇ and R₈ taken together form a 3-8 membered ring; or R₇ and R₈ taken together form a 4-8 membered ring; R₉ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀, —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or acylthio; R₆ is H or alkyl; each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; R₁₄ is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl; R₁₆ is H, alkyl, alkenyl, or OR₁₁; has the formula 4a; each of X³ independently for each occurrence is H or halide; R₁₈ is alkyl, alkenyl, halide, nitro, or amino; each of R₂₀ and R₂₁ is independently H, alkyl, aralkyl, heteroaralkyl, alkoxy, or —[C(R₂₂)(R₂₃)]₁—R₂₄; t is independently for each occurrence 1, 2, 3, 4, or 5; each of R₂₂ and R₂₃ is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and R₂₄ is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.
 5. The compound of claim 4, wherein Y is —(C═O)— and X is —NH—.
 6. The compound of claim 4, wherein B has the formula 6a or 6b:

wherein p is 0, 1, or 2; each of R₇ and R₈ independently for each occurrence is H or alkyl; and R₉ is H, —OR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —OCO₂R₁₀, or —OC(O)N(R₁₀)₂.
 7. The compound of claim 4, wherein B is S.
 8. The compound of claim 4, wherein A₁ and A₂ taken together form ═O and B has the formula 8:

wherein p is 0, 1 or 2; each of R₇ and R₈ independently for each occurrence is H or alkyl; and R₉ is H, —OR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —OCO₂R₁₀, or —OC(O)N(R₁₀)₂.
 9. The compound of claim 8, wherein A₁ and A₂ are each H.
 10. A compound represented by formula 10:

or an unsaturated form thereof or a pharmaceutically acceptable salt thereof; wherein m represents independently for each occurrence 0, 1, 2, 3, 4, 5, or 6; A is —S(O)—, —S(O)₂—,

or —C(A₁)(A₂)-; each of A₁ and A₂ is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R₁₀)₂, —C(O)R₁₀, —CO₂R₁₀, —S(O)₂N(R₁₀), —S(O)R₁₀, —S(O)₂OR₁₀, or —S(O)₂R₁₀; or has the formula 10a:

wherein independently for each occurrence of 10a; n is 1, 2, 3, 4, 5, or 6; and R₁₅ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, or —C(O)N(R₁₀)₂; or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N; or A₁ and A₂ taken together form ═O or ═S; or A₁ and A₂ taken together with the carbon to which they are attached form a 5 to 8 heterocyclyl, of which one or two ring atoms are independently S, O or N B is O, S, —(C═O)—, —(C═S)— or,

or has the formula 10b:

wherein D is N or CR₁₀; p is0, 1, 2, 3,4, or 5; each of R₇ and R₈ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heteroaryl; or R₇ and R₈ taken together form a 3-8 membered ring; or R₇ and R₈ taken together form a 4-8 membered ring; R₉ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀, —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or acylthio; R₁ has the formula 10c or 10d:

wherein q is 0, 1, 2, 3, 4, or 5; r is 0, 1, 2, 3, 4, or 5; W is a bond; or alkyl diradical, alkenyl diradical, or alkynyl diradical; Z is H, —SR₁₀, —S(O)₂R₁₁, —NR₁₀S(O)₂R₁₁, —S(O)R₁₀, —N(R₁₀)(R₁₁), —C(O)R₁₁, —CO₂R₁₁, —C(O)N(R₁₀)(R₁₁), —C(S)N(R₁₀)(R₁₁), —CH₂C(O)heterocyclyl, —NR₁₀C(O)R₁₁, —NR₁₀CO₂R₁₁, —OC(O)N(R₁₀)(R₁₁), —NC(O)CH(R₁₀)(R₁₁), —C(═NR₁₀)N(R₁₀)(R₁₁), —C(═NR₁₀)R_(11,) hydroxyalkyl, monocyclic aryl, bicyclic aryl, heteroaryl, or heterocyclyl; Ar¹ is a monocyclic or bicyclic aryl with 6-14 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N; or Ar¹ is represented by formula 10e:

Wherein s is 0, 1, 2, 3, or 4; each of X² and X³ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, OR₁₁, —C(O)N(R₁₀)(R₁₁), —C(O)R₁₁, —CO₂R₁₁, —S(O)₂N(R₁₀)(R₁₁), SR₁₁, —S(O)R₁,, —S(O)₂OR₁₁ , —S(O)₂R₁₁, —C(═NR₁₀)N(R₁₀)(R₁₁), or —C(═NR₁₀)(R₁₁); or has the formula 10a; Ar² represent independently for each occurrence are monocyclic or bicyclic aryl with 6-14 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N; X¹ is a bond, —C(R₁₀)₂—, —S—, —N(R₁₀)— or —O—; R₂ is H, a branched or unbranched alkyl or alkenyl, cycloalkyl, heterocyclyl, orbicycloalkyl; or has the formula 10a: R₃is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀, —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or acylthio; each of R₄, R₅ and R₁₀ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 10a; or any two instances of R₁₀ taken together form a 3-8 membered ring; or R₄ and R₅ taken together form a 3-8 membered ring; R₆ is H or alkyl; R₁₁ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R₁₂)(R₁₃)]₁—R₁₄; wherein t is 0, 1, 2, 3, 4, or 5; each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and R₁₄ is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.
 11. The compound of claim 10, wherein R₁ has the formula 11:

wherein s is 0, 1, 2, 3, or 4; each of X³ is independently for each occurrence H or halide; each of R₁₈ and R₁₉ is independently H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R₁₂)(R₁₃)]₁—R₁₄; wherein t is 1, 2, 3, 4, or 5; each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and R₁₄ is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.
 12. The compound of claim 10, wherein B has the formula 12a or 12b:

wherein p is 0, 1, 2, 3, or 4; each of R₇ and R₈ is independently for each occurrence H or alkyl; and R₉ is H, —OR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —OCO₂R₁₀, or —OC(O)N(R₁₀)₂.
 13. The compound of claim 10, wherein A is —C(A₁)(A₂)-; A₁ and A₂ taken together form ═O and B has the formula 13:

wherein p is0, 1, 2, 3, or 4; each of R₇ and R₈ independently for each occurrence is H or alkyl; and R₉ is H, —OR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —OCO₂R₁₀, or —OC(O)N(R₁₀)₂.
 14. A compound represented by formula 14:

or an unsaturated form thereof or a pharmaceutically acceptable salt thereof; wherein Y is —C(R₁₀)₂—, —(C═O)—, —(C═S)—, or —C(═NR₁₀)—; X is —N(R₁₀)—, or a bond; m represents independently for each occurrence 0, 1, 2, 3, 4, 5, or 6; A is —S(O)—, —S(O)₂—,

or —C(A₁)(A₂)-; each of A₁ and A₂ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R₁₀)₂, —C(O)R₁₀, —CO₂R₁₀, —S(O)₂N(R₁₀)₂, —S(O)R₁₀, —S(O)₂OR₁₀, —S(O)₂R₁₀; or has the formula 14a:

wherein independently for each occurrence of 14a; n is 1, 2, 3, 4, 5, or 6; and R₁₅ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, or —C(O)N(R₁₀)₂; or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N; or A₁ and A₂ taken together form ═O or ═S; or A₁ and A₂ taken together with the carbon to which they are attached form a 5 to 8 heterocyclyl, of which one or two ring atoms are independently S, O or N; B is —(C(R)₂X)—, —(XC(R)₂)—, or - (C(R)₂)₂—; X independently for each occurrence is S, —(NR₁₀)—, or —O—; R independently for each occurrence is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl; or has formula 14a; R₁ has the formula 14b:

wherein q is 1, 2, 3, 4, or 5; r is 0, 1, 2, 3, 4, or 5; Ar¹ is a monocyclic or bicyclic aryl with 6-14 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N; or Ar is represented by formula 14c:

Wherein s is 0, 1, 2, 3, or 4; each of X² and X³ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, —OR₁₁, —C(O)N(R₁₀)(R₁₁), —C(O)R₁₁, —CO₂R₁₁, —S(O)₂N(R₁₀)(R₁₁), —SR₁₁, —S(O)R₁₁, —S(O)₂OR₁₁, —S(O)₂R₁₁, —C(═NR₁₀)N(R₁₀)(R₁₁), or —C(═NR₁₀)(R₁₁); or has the formula 14a; Ar² represent independently for each occurrence are monocyclic or bicyclic aryl with 6-14 ring atoms; or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N; X¹ is a bond, —(C(R₁₀)₂)—, —S—, -(NR₁₀)—, or —O—; R₂ is H, a branched or unbranched alkyl or alkenyl, cycloalkyl, heterocyclyl, or bicycloalkyl; or has the formula 14a: R₃ is H, heterocyclyl, heteroaryl, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —N(R₁₀)CO₂R₁₀, —N(R₁₀)C(O)N(R₁₀)₂, —CO₂R₁₀, —OCO₂R₁₀, —OC(O)N(R₁₀)₂, —C(O)N(R₁₀)₂, halide, nitrile, nitro, or acylthio; each of R₄, R₅ and R₁₀ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, or heteroaryl; or has the formula 14a; or any two instances of R₁₀ taken together form a 3-8 membered ring; or R₄ and R₅ taken together form a 3-8 membered ring; R₆ is H or alkyl; R₁₁ independently for each occurrence is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R₁₂)(R₁₃)]₁—R₁₄; wherein t is 0, 1, 2, 3, 4, or 5; each of R₁₂ and R₁₃ is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl; and R₁₄ is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.
 15. The compound of claim 14, wherein the compound has the formula 15:


16. The compound of claim 14, wherein the compound has the formula 16:


17. A compound selected from the group consisting of:


18. A pharmaceutical composition, comprising a compound of claim 1, 10, 14, or 17; and at least one pharmaceutically acceptable excipient.
 19. A method of treating cancer, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, 10, 14, or
 17. 20. A method of treating cancer, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of one or more chemotherapeutic agents; and a therapeutically effective amount of a compound of claim 1, 10, 14, or
 17. 